Home Blog of Signal Transduction Protein Tyrosine Kinase IGF-1R Sperm-carried IGF2 downregulated the expression of mitogens produced by Sertoli cells: A paracrine mechanism for regulating spermatogenesis?

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Sperm-carried IGF2 downregulated the expression of mitogens produced by Sertoli cells: A paracrine mechanism for regulating spermatogenesis?

Introduction: Insulin-like growth factor 2 (IGF2) mRNA has been found in human and mouse spermatozoa. It is currently unknown whether the IGF2 protein is expressed in human spermatozoa and, if so, its possible role in the cross-talk between germ and Sertoli cells (SCs) during spermatogenesis.

Methods: To accomplish this, we analyzed sperm samples from four consecutive Caucasian men. Furthermore, to understand its role during the spermatogenetic process, porcine SCs were incubated with increasing concentrations (0.33, 3.33, and 10 ng/mL) of recombinant human IGF2 (rhIGF2) for 48 hours. Subsequently, the experiments were repeated by pre-incubating SCs with the non-competitive insulin-like growth factor 1 receptor (IGF1R) inhibitor NVP-AEW541. The following outcomes were evaluated: 1) Gene expression of the glial cell-line derived neurotrophic factor (GDNF), fibroblast growth factor 2 (FGF2), and stem cell factor (SCF) mitogens; 2) gene and protein expression of follicle-stimulating hormone receptor (FSHR), anti-Müllerian hormone (AMH), and inhibin B; 3) SC proliferation.

Results: We found that the IGF2 protein was present in each of the sperm samples. IGF2 appeared as a cytoplasmic protein localized in the equatorial and post-acrosomal segment and with a varying degree of expression in each cell. In SCs, IGF2 significantly downregulated GDNF gene expression in a concentration-dependent manner. FGF2 and SCF were downregulated only by the highest concentration of IGF2. Similarly, IGF2 downregulated the FSHR gene and FSHR, AMH, and inhibin B protein expression. Finally, IGF2 significantly suppressed the SC proliferation rate. All these findings were reversed by pre-incubation with NVP-AEW541, suggesting an effect mediated by the interaction of IGF2 with the IGFR.

Conclusion: In conclusion, sperm IGF2 seems to downregulate the expression of mitogens, which are known to be physiologically released by the SCs to promote gonocyte proliferation and spermatogonial fate adoption. These findings suggest the presence of paracrine regulatory mechanisms acting on the seminiferous epithelium during spermatogenesis, by which germ cells can influence the amount of mitogens released by the SCs, their sensitivity to FSH, and their rate of proliferation.

 

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**Summary:**

The study investigated the presence and role of Insulin-like growth factor 2 (IGF2) protein in human spermatozoa and its impact on the communication between germ cells and Sertoli cells (SCs) during spermatogenesis. The research involved analyzing sperm samples from four men and conducting experiments using porcine SCs incubated with recombinant human IGF2 (rhIGF2). The findings revealed that IGF2 protein was present in human sperm, primarily in specific segments of the sperm cell. In SCs, IGF2 downregulated the expression of various mitogens (GDNF, FGF2, SCF) and reproductive hormones (FSHR, AMH, inhibin B) and suppressed SC proliferation. These effects were reversed by pre-incubation with an IGF1R inhibitor, indicating the involvement of IGF2-IGFR interaction. The results suggest the presence of regulatory mechanisms in spermatogenesis where germ cells influence mitogen release, FSH sensitivity, and SC proliferation by interacting with SCs.

**Key Findings:**

1. **IGF2 Presence in Sperm:** IGF2 protein was identified in human spermatozoa, localized in specific segments of the cell.

2. **IGF2 Impact on SCs:**
   - IGF2 downregulated the expression of mitogens (GDNF, FGF2, SCF) in SCs.
   - It also decreased the expression of reproductive hormones (FSHR, AMH, inhibin B) in SCs.
   - IGF2 suppressed the proliferation rate of SCs.

3. **Reversal by IGF1R Inhibitor:** Pre-incubation with NVP-AEW541, an IGF1R inhibitor, reversed the effects of IGF2, indicating that the actions were mediated through IGF2-IGFR interaction.

**Conclusion:**

The study suggests that sperm IGF2 influences the expression of mitogens released by SCs, affecting gonocyte proliferation and spermatogonial fate. These findings indicate the presence of paracrine regulatory mechanisms in the seminiferous epithelium, where germ cells modulate mitogen release, FSH sensitivity, and SC proliferation during spermatogenesis.

Related Products

Cat.No. Product Name Information
S1034 NVP-AEW541 NVP-AEW541 is a potent inhibitor of IGF-1R/InsR with IC50 of 150 nM/140 nM in cell-free assays, greater potency and selectivity for IGF-1R in a cell-based assay.

Related Targets

IGF-1R